Novartis data show ACZ885 delivered rapid and strong symptom relief while reducing frequency of attacks in two periodic fever syndromes

• New Phase II study shows monthly ACZ885 reduced attack frequency by >= 50% and normalized inflammation markers in Familial Mediterranean Fever patients[1]

 

• ACZ885 also provided sustained symptom relief in patients with TNF-receptor associated periodic syndrome as shown in new data from another Phase II study[2]

 

• Children and adults with these rare autoinflammatory diseases can experience debilitating attacks of fever and painful symptoms, including arthritis[3]

Basel, November 11, 2012 - Novartis announced today new data from two Phase II trials of ACZ885 (canakinumab), in patients with one of two rare syndromes characterized by periodic fevers. Key findings include reductions in disease attack frequency[1], maintenance of symptom relief[2], normalization of blood markers of inflammation, and quality of life improvements[2]. Both rare orphan diseases, Familial Mediterranean Fever (FMF) and tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), are serious, inherited autoinflammatory diseases characterized by recurrent (periodic) fever attacks, rash, arthritis, and severe symptoms that can lead to fatal complications[3-7].

"During attacks, patients suffering with these periodic fever syndromes can be incapacitated with pain and fever," said Dr Ahmet Gül, lead FMF study investigator and Professor of Rheumatology at the Istanbul Faculty of Medicine, in Istanbul, Turkey. "Although rare, these syndromes have a serious impact on the patients and families by limiting their ability to participate in daily life during an attack, so it is critically important to research new treatment options that can neutralize the underlying inflammation, and help patients to live a normal life."

The results of the two ACZ885 studies, which met their primary endpoints, are being presented at the 2012 Annual Scientific Meeting of the American College of Rheumatology (ACR) in Washington D.C., US, which takes place on 9-14 November[1,2]. ACZ885 inhibits interleukin-1 beta (IL-1 beta), which plays a key role in several debilitating autoinflammatory diseases, including rare periodic fever syndromes[8,9].

"The role of IL-1 beta as a key player in a number of serious autoinflammatory conditions is becoming ever clearer", said John Hohneker, Head of Global Development for Integrated Hospital Care for the Pharmaceuticals Division of Novartis. "We are dedicated to realizing the potential of ACZ885, wherever alternative treatment options fail to appropriately help patients and whenever a strong scientific rationale comes into play."

In the Phase II FMF study, 100% of patients (nine out of nine) achieved at least a 50% reduction in the frequency of disease attacks during three months of ACZ885 treatment[1]. All nine patients in the trial had previously experienced at least one attack per month over three months before receiving ACZ885, while using standard-of-care medication[1]. During the three-month ACZ885 treatment period, eight of the nine patients were attack-free, while blood markers of inflammation (C-reactive protein, CRP, and serum amyloid A, SAA) normalized by Day 8 after ACZ885 dosing and remained low throughout the study[1]. The overall response to treatment was reported to be 'very good' by physicians in all cases, and by the patients in seven cases[1].

New data from the Phase II study in TRAPS showed that after rapid clinical remission and normalization of CRP and/or SAA, which was maintained with continued ACZ885 treatment, the median time to relapse after ACZ885 withdrawal was three months[2]. Patients also regained their previous response upon re-dosing with ACZ885[2]. Prior to study entry, patients experienced a mean of 10 attacks per year[2]. When assessed during the initial four-month ACZ885 treatment period, patients experienced improvements in both physical and mental measures of quality of life[2].

Adverse events (AEs) observed in the studies were similar to those already seen for ACZ885's approved indication in Cryopyrin-Associated Periodic Syndromes (CAPS). Infections, mostly upper respiratory tract infections (URIs) were the most commonly reported category of AE in both the FMF and TRAPS studies[1,2]. No serious adverse events (SAEs) were reported in the FMF study[1]; while in the TRAPS study, two SAEs were reported: a URI that lasted two days and a severe disease attack with chest pain[2].

About the studies

ACZ885 in FMF

The Phase II, open-label, single-centre study investigating the efficacy and safety of ACZ885 in patients with colchicine-resistant FMF involved nine patients with a median age of 22 years (range, 12-34 years)[1]. The patients, who had experienced >= 1 FMF attack per month in the three months before receiving ACZ885 (the run-in period), received ACZ885 150 mg every four weeks[1]. Treatment began at the start of the first attack during the initial study month[1].

The primary endpoint of the study was a >=50% reduction in attack frequency over three months[1]. Eight out of nine patients had at least one AE reported. All AEs were mild or moderate in severity, except one severe headache[1].

ACZ885 in TRAPS

The ongoing Phase II, open-label, multicenter study investigating the efficacy and safety of ACZ885 in patients with active TRAPS involves 20 patients with a median age of 39 years (range, 7-78 years)[2]. In the first phase, patients received ACZ885 150 mg (or increased to 300 mg for those without complete or almost complete response by Day 8) every four weeks for four months[2]. This was followed by a second, treatment withdrawal, phase of up to five months where the patients restarted ACZ885 treatment upon their first relapse[2]. The third, ongoing, phase is a 24-month period involving open-label treatment every four weeks[2].

The primary endpoint of the study is complete or almost complete response at Day 15[2]. Ninety percent of patients with TRAPS treated with ACZ885 experienced clinical remission (absent or minimal signs and symptoms of TRAPS) after one week of treatment, and two patients had their dose increased to 300 mg[2]. After two weeks of treatment, 100% of patients achieved clinical remission and 95% of patients had achieved a complete or almost complete response, which was maintained until the end of treatment with monthly dosing[2].

Complete response was defined as clinical remission and normal CRP and/or SAA levels[2]. Almost complete response was defined as clinical remission and >=70% reduction of baseline CRP and/or SAA[2]. Clinical remission was maintained for all patients from Day 15 onwards in the four month treatment period, except for one patient with a relapse at Day 85 who subsequently responded to the scheduled ACZ885 dose[2].

All patients had at least one AE reported, and most AEs were mild in severity[2].

About ACZ885

ACZ885 is a fully human monoclonal antibody that inhibits IL-1 beta, which is an important part of the body's immune system defenses[10]. Excessive production of IL-1 beta plays a major role in certain inflammatory diseases, including FMF[1] and TRAPS[2]. ACZ885 works by neutralizing IL-1 beta for a sustained period of time, thereby inhibiting inflammation[10].

Under the brand name Ilaris®, ACZ885 is approved in more than 60 countries, including in the EU, US and Switzerland for the treatment of adults and children as young as four years with CAPS, a rare, lifelong, inflammatory disorder with debilitating symptoms[10]. ACZ885 is also being studied in other diseases in which IL-1 beta plays a key role in causing inflammation, such as gouty arthritis, systemic juvenile idiopathic arthritis (SJIA) and cardiovascular disease. ACZ885 is not approved for the treatment of FMF or TRAPS. Not all potential patients with these diseases would be eligible for treatment with ACZ885, if approved for the applicable disease.

About the two periodic fever syndromes: FMF and TRAPS

TRAPS and FMF are rare, genetically inherited, autoinflammatory periodic fever syndromes that can affect both children and adults[3,5-7]Patients with TRAPS suffer long and intermittent attacks that can involve fever, rash, abdominal pain, conjunctivitis, inflammation around the eyes and severe joint pain[3,5,6] FMF causes patients to experience shorter episodes that also include fever, rash and painful inflammation that affects the joints and abdomen[4,8]. Amyloidosis is a serious long-term complication estimated to occur in 25% of patients with TRAPS[11], and 50-60% of untreated patients with FMF[12]. It can lead to liver or kidney failure, and in some instances, amyloidosis can be fatal[13,14]

In addition to living with debilitating symptoms, the lives of patients and their families can be seriously disrupted by the unpredictable, periodic disease attacks associated with TRAPS and FMF[15,16]. Difficulties in reaching a diagnosis can lead to both anxiety and unnecessary medical procedures[15,16].

There are currently no approved treatments for TRAPS or FMF. While nonsteroidal anti-inflammatory drugs, steroids and colchicine have been shown to relieve some symptoms in TRAPS, there can be problems with limited and intermittent efficacy[5], in addition to the side-effects of long-term steroid use, particularly in children[17]. Colchicine has also been used to treat patients with FMF, but the response can be low or absent in approximately 10-15% of cases[18]. Genes that encode proteins involved in the regulation of interleukin-1 beta (IL-1 beta) have been implicated in both diseases[8,19,20].

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as "can," "dedicated," "potential," "would," or similar expressions, or by express or implied discussions regarding potential new indications or labeling for ACZ885 or regarding potential future revenues from ACZ885. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with ACZ885 to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that ACZ885 will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that ACZ885 will achieve any particular levels of revenue in the future. In particular, management's expectations regarding ACZ885 could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; government, industry and general public pricing pressures; competition in general; unexpected manufacturing difficulties; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis

Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2011, the Group achieved net sales of USD 58.6 billion, while approximately USD 9.6 billion (USD 9.2 billion excluding impairment and amortization charges) was invested in R&D throughout the Group. Novartis Group companies employ approximately 127,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.

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References

[1] Grandemange S, Aksentijevich I, Jeru I, Gul A, Touitou I. The regulation of MEFV expression and its role in health and familial Mediterranean fever. Genes Immun; 12(7):497-503.

[2] Ozgocmen S, Akgul O. Anti-TNF agents in familial Mediterranean fever: report of three cases and review of the literature. Modern Rheumatology; 21(6):684-90.

[3] Simon A, van der Meer JW. Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes. Am J Physiol Regul Integr Comp Physiol 2007; 292(1):R86-98.

[4] Shohat M, Halpern GJ. Familial Mediterranean fever--a review. Genet Med 2011; 13(6):487-98.

[5] Fietta P. Autoinflammatory diseases: the hereditary periodic fever syndromes. Acta Biomed 2004; 75(2):92-9.

[6] Borghini S, Fiore M, Di Duca M, et al. Candidate genes in patients with autoinflammatory syndrome resembling tumor necrosis factor receptor-associated periodic syndrome without mutations in the TNFRSF1A gene. J Rheumatol 2011; 38(7):1378-84.

[7] Grandemange S, Aksentijevich I, Jeru I, Gul A, Touitou I. The regulation of MEFV expression and its role in health and familial Mediterranean fever. Genes Immun 2011; 12(7):497-503.

[8] Savic S, Dickie LJ, Battellino M, McDermott MF. Familial Mediterranean fever and related periodic fever syndromes/autoinflammatory diseases. Curr Opin Rheumatol 2012; 24(1):103-12.

[9] Church LD, Cook GP, McDermott MF. Primer: inflammasomes and interleukin 1beta in inflammatory disorders. Nat Clin Pract Rheumatol 2008; 4(1):34-42.

[10] Ilaris [precribing information]. Surrey, UK: Novartis Pharmaceuticals UK Ltd; 2011.

[11] Dode C, Cuisset L, Delpech M, Grateau G. TNFRSF1A-associated periodic syndrome (TRAPS), Muckle-Wells syndrome (MWS) and renal amyloidosis. J Nephrol 2003; 16(3):435-7.

[12] Ben-Zvi I, Danilesko I, Yahalom G, et al. Risk factors for amyloidosis and impact of kidney transplantation on the course of familial Mediterranean fever. Isr Med Assoc J 2012; 14(4):221-4.

[13] Aksentijevich I, Galon J, Soares M, et al. The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers. Am J Hum Genet 2001; 69(2):301-14.

[14] Nussinovitch U, Ben-Zvi I, Livneh A. QT variability in amyloidosis of familial Mediterranean fever. Isr Med Assoc J 2012; 14(4):225-8.

[15] PRINTO. Familial Mediterranean Fever. Available at: http://www.printo.it/pediatric-rheumatology/information/UK/pdf/13_6_FMF_UK.pdf Accessed on 24 October, 2012.

[16] PRINTO. Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) or familial Hibernian fever. Available at: http://www.printo.it/pediatric-rheumatology/information/UK/pdf/13_11_TRAPS%20_UK.pdf Accessed on 24 October, 2012.

[17] Doull IJ, Campbell MJ, Holgate ST. Duration of growth suppressive effects of regular inhaled corticosteroids. Arch Dis Child 1998; 78(2):172-3.

[18] Cerquaglia C, Diaco M, Nucera G, La Regina M, Montalto M, Manna R. Pharmacological and clinical basis of treatment of Familial Mediterranean Fever (FMF) with colchicine or analogues: an update. Curr Drug Targets Inflamm Allergy 2005; 4(1):117-24.

[19] Henderson C, Goldbach-Mansky R. Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis. Curr Opin Rheumatol 2010; 22(5):567-78.

[20] Nedjai B, Hitman GA, Quillinan N, et al. Proinflammatory action of the antiinflammatory drug infliximab in tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 2009; 60(2):619-25.

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Posted: November 2012

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